Oral care formulation and method for the removal of tartar and plaque from teeth

ABSTRACT

An oral care formulation and method for removing tartar and plaque from the teeth, gums, and oral cavity is disclosed. The oral care formulation can take the form of a toothpaste, gel, wash, rinse, soak, spray, chewing gum, dental floss, or other suitable delivery system, containing a therapeutically effective amount of dimethyl isosorbide (DMI) (or equivalent or analog thereof) and chlorine dioxide (ClO 2 ) for removal of tartar and plaque.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/538,121, which is a 35 USC § 371 national stage ofPCT/U2016/066875, filed Dec. 15, 2016, and claims the benefit of U.S.Provisional Patent Application No. 62/287,538, filed Jan. 27, 2016, andU.S. Provisional Patent Application No. 62/267,354, filed Dec. 15, 2015,all of which are incorporated herein by reference as if fully set forth.

FIELD

An oral care formulation and method for removing tartar and plaque fromthe teeth, gums, and oral cavity is provided. The oral care formulationcan take the form of a toothpaste, gel, wash, rinse, soak, spray,chewing gum, dental floss, or other suitable delivery system, containinga therapeutically effective amount of dimethyl isosorbide (DMI) (orequivalent or analog thereof) and chlorine dioxide (ClO₂) for removal oftartar and plaque.

BACKGROUND

Over the years, numerous consumer products have been manufactured andmarketed for cleansing teeth of tartar and plaque. The products havetaken the form of toothpastes, powders, gels, liquid rinses, chewinggum, dental floss, or other suitable delivery systems. The formation oftartar and plaque on clean teeth is a complex process, which begins withbacteria in the mouth.

This process begins within a few minutes after the teeth have beenprofessionally cleaned by a dentist or hygienist. The first bacteriastart attaching to the pellicle on the tooth surface, tongue, and gums.This first layer of bacteria allows other bacteria to attach. Thesebacteria then multiply by cell division to form a complex structurecalled a biofilm. After two to three hours, the biofilm thicknessincreases to the point that a visible film of bacteria can be seen bythe naked eye.

This visible film of bacteria is called plaque and, over time, thebacteria in protected areas of the mouth grow into thick structuresknown as mature plaque. If this plaque is not disturbed by flossing orbrushing, it begins to mineralize as calcium and phosphate ions fromsaliva start to deposit within the bacterial colony and harden to formcrystalline tartar. Most toothpaste achieves their cleaning action fromabrasives which can comprise about 50% of the typical toothpaste. Theseinsoluble abrasives help remove plaque from accessible portions of theteeth. Brushing, however, will not remove tartar. Traditional toothpasteand other traditional mouth rinses can help prevent tartar buildup, butthey cannot remove it once it has formed. Until now, only a dentalhygienist or dentist could remove tartar by physically scraping it fromthe tooth surface with specialized metal instruments. The physicalprocess by which a dentist or hygienist scrapes tartar from teeth iscalled “scaling.” During a scaling, the dentist or hygienist usesspecial stainless steel instruments to remove tartar from the teeth bothabove and below the gum line.

Dental plaque is a biofilm (usually a pale yellow to whitish color) thatbuilds up on the surface of teeth. If not removed regularly, it can leadto dental cavities (caries) or periodontal problems (such asgingivitis). The microorganisms that form the biofilm are almostentirely bacteria (mainly Streptococcus and anaerobes), with thecomposition varying by location in the mouth. The microorganisms presentin dental plaque are all naturally present in the oral cavity, and arenormally harmless. However, failure to remove plaque allows it to buildup in a thick layer and leads to increased bacterial growth.

Dental plaque is a precursor of tartar, which is also known as calculus.Both terms, “tartar” and “calculus,” are used interchangeably to referto mineralized dental plaque, where the mineral may be calcium. Thisbuild-up of hardened (mineralized) plaque on the teeth is formed by thepresence of saliva, debris, glucans, and minerals. Typically tartar isprimarily comprised of four or more calcium phosphate mineral salts,including octacalcium phosphate, hydroxyapatite, whitlockite, andbrushite. These salts are deposited within and between remnants of thebiofilm and plaque bacterial colony. Mature tartar consists of aninorganic portion which is largely calcium phosphate arranged in ahydroxyapatite crystal lattice structure similar to bone, enamel, anddentine. An organic portion is also present and consists of desquamatedepithelial cells, leukocytes, glucans, salivary sediment, food debris,and various types of microorganisms. The rough surface of mature tartarprovides an ideal medium for bacterial growth, threatening the health ofthe gums and absorbing unaesthetic stains far more easily than naturalteeth.

The longer that tartar, plaque, and the bacteria they protect remain onthe teeth, the more damage they can cause. Initially, accumulation oftartar, plaque, and bacteria may simply irritate and inflame thegingiva, the part of the gum around the base of the teeth. This iscalled gingivitis, the mildest form of periodontal disease. Ongoinginflammation eventually causes pockets to develop between the gums andteeth that fill with plaque, tartar and bacteria. Bacteria can depositendotoxins—a byproduct of their own metabolism—which are responsible formuch of the inflammation that can be caused around teeth. In time, thesepockets in the gums become deeper and, as more bacteria accumulate,eventually advance under the gum tissue. These deep infections can causea loss of tissue and bone. If too much bone or tissue is destroyed, oneor more teeth may be lost.

There are two basic forms of tartar. Supragingival (outside the gums)tartar is the visible deposit that forms on the top of the teeth.Subgingival (inside the gums) tartar forms in pockets between teeth andgums. Subgingival tartar is more harmful because it promotes fastergrowth of bacteria. Buildup of tartar often causes swelling, bleedingand weakening of gums, and can lead to gum recession and tooth loss.Tartar can even extend into pockets created between the teeth and gums.The anaerobic bacteria found in pockets around teeth may be linked tocardiovascular disease and pre-term low birth weight babies. Thesepockets are difficult to reach by tooth brushing, and are not affectedby standard mouthwashes.

Regularly scheduled teeth cleanings every six months with a dentist ordental hygienist where scaling of the teeth is performed can beeffective for the removal of accumulated tartar and plaque. Schedulingregular professional dental cleanings, however, can be difficult inareas where access to a dental professional is limited or the demands ofbusy schedules require the cancellation or postponement of professionalteeth cleanings. Moreover, certain individuals can be geneticallypredisposed to the rapid formation and accumulation of tartar, whichrequires more frequent (usually every three months) professional dentalcleanings than the typical six-month interval.

Although the mechanical dental scaling procedure may be effective intartar removal, in addition to being very time-consuming, this procedurehas several disadvantages. One disadvantage of dental scaling is thatthe process can destroy dental cementum, which is a tooth formationcritical to gum/tooth attachment. Another disadvantage of dental scalingis that the treatment may remove healthy gum tissue, which cannotregenerate. Still another disadvantage is that the procedure is painfuland often causes bleeding and swelling of the gums when tartaraccumulation is substantial. An economic disadvantage is that dentalscaling is almost exclusively done by a dental professional and isrelatively expensive.

A variety of chemical and biological agents have been suggested toretard tartar formation. Pyrophosphate salts and other chemical agentsare known to have the ability to retard tartar formation. Currentanti-tartar oral formulations designed for preventing the accumulationof tartar on the teeth often incorporate as an active ingredient sodiumpyrophosphate, tetrasodium pyrophosphate, or other types ofpyrophosphate compounds to prevent calcium phosphate salts fromdepositing on the enamel of teeth. One example can be found in U.S. Pat.No. 8,303,938. Compounds containing pyrophosphate, however, can resultin tooth sensitivity and mouth lesions in some individuals. Moreover,none of the anti-tartar oral formulations containing pyrophosphatecompounds are very effective at actively removing tartar from teeth oncethe calcium phosphate salts have bonded with tooth enamel.

Other chemicals reportedly have been used to inhibit the formation ofplaque and calculus on teeth. For example, in U.S. Pat. No. 4,610,871describes the use of monoalkyl or dialkyl ethers of dianhydrohexitols toinhibit the formation of plaque and calculus on teeth is described. U.S.Pat. No. 4,178,363 describes the use of n-undecylenic acid or a calciumor zinc salt thereof for reducing dental plaque and infections of theteeth and gums. U.S. Pat. No. 4,119,711 describes spiro 1-(hydroxyalkyl)piperidino derivatives, which have efficacy in reducing the formation ofplaque. Additionally, U.S. Pat. No. 3,887,712 discloses that alexidinedihydrofluoride is useful in the treatment of dental plaque, calculus,gingivitis, and related periodontal diseases. U.S. Pat. No. 4,160,821discloses that a glycerin solution of zinc chloride or other acceptablezinc salts provides effective therapy for gingivitis when applied to thegingival and teeth. U.S. Pat. No. 4,060,600 teaches a method of treatingteeth in dentistry, for the prevention of calculus, removal of caries,and dissolution of plaque, comprising applying an aqueous solutioncontaining a hypochlorite of an alkali and/or alkaline earth metal, andan amino compound capable of forming water-soluble non-mucous irritatingN-chloro and/or N-dichloro derivatives thereof to the teeth. All ofthese chemical and biological agents have some disadvantages, such aslimited effectiveness, discoloration of teeth or tongue, desquamationand soreness of oral mucosa, objectionable taste, toxicity, and may alsocause an imbalance of the oral flora.

Dimethyl isosorbide (DMI) is a hydrophilic and highly polar compound.DMI is a non-toxic solvent and carrier that is considered to be neithera primary irritant to human skin nor a skin sensitizer. DMI alsoprovides a safe and effective delivery enhancement mechanism for activeingredients in skin care products, such as sunless tanners, facial andeye-zone treatments, skin serums, anti-acne formulations and make-upremovers.

DMI was studied in the 1980's for use in dentifrices and oral careformulations for inhibiting the formation of plaque and calculus in themouth (Lynch U.S. Pat. Nos. 4,585,649; 4,610,871; and 4,627,974). Lynchdemonstrated that DMI has antibacterial properties against Streptococcusmutans and that DMI is a weak antibacterial at high concentrations.Lynch also observed that collected dental tartar was slowly dissolved byDMI in an occasionally stirred beaker over a 24 hour period at 100% and50% aqueous concentrations. Lynch, however, did not provide any findingsconcerning whether DMI was capable of in vivo removal of tartar fromteeth and gums.

DMI was considered for use as an antibacterial for oral applications inthe 1980's and was heavily marketed into the personal care and oralhealth industries in the Americas, Europe, Australia, and Japan. DMI hasbeen found to be an excellent delivery enhancer, which can place activeingredients where they are needed most on the skin. This functionalityof DMI has been used in sunless tanners, facial and eye-zone treatments,skin serums, anti-acne formulations and make-up removers. In oralhygiene applications, DMI has found little if any use as a deliveryenhancer in oral applications.

Originally, DMI was thought to have use as an antibacterial in oralapplications, but its antibacterial functionality is weak and moreeffective anti-bacterials such as Triclosan(5-chloro-2-(2,4-dichlorophenoxy)phenol), chlorohexidine gluconate, andzinc and other metal salts are used as antibacterials in oralapplications. As described above, DMI has shown some utility indissolving tartar in vitro over a period of 24 hour, sustained exposurein the Lynch U.S. Pat. Nos. 4,627,974 and 4,610,871, but was noteffective at removing tartar from subjects' teeth in vivo. DMI is alsorelatively expensive at nearly $100.00 per kilogram for personal careproducts. Where it is found in products, it is usually present in the0.1% (w) to 2% (w) levels. Thus, DMI is only considered for high valuedelivery enhancement application in the personal care industry.Moreover, industry had largely abandoned research and the use of DMI inthe oral hygiene setting as an unsuccessful, limited spectrum, oralantiseptic that was cost-prohibitive. There currently are no knowncommercial toothpastes or mouthwashes containing DMI for sale on thedental care market.

Chlorine dioxide (ClO₂) is a highly soluble gas that does not hydrolyzewhen combined with water. Instead, it remains dissolved as a gas insolution. Chlorine dioxide has been used as a powerful and safedisinfectant and biocide for almost 200 years, including for manyindustrial applications. More recently, chlorine dioxide has been usedfor removing bacteria and biofilm from cooling towers and potable waterlines. When applied correctly, it has been shown to control a broadrange of biofilms and bacteria.

Chlorine dioxide is strongly oxidizing and can be explosive inconcentrations exceeding 10% (v/v). Because “active” chlorine dioxide,ClO₂, is highly reactive with other chemicals, it is often converted toa stabilized form for transporting and mixing, as described inMcNicholas U.S. Pat. No. 3,271,242. Active chlorine dioxide can also beprepared at the time of use by combining chlorite source (for examplesodium chlorite, potassium chlorite, or calcium chlorite) with a weakfood or cosmetic grade acid (for example, citric acid, lactic acid,sodium bisulfate, or disodium phosphate), which produces chlorous acidas an intermediate, which in turn forms active chlorine dioxide.Stabilized chlorine dioxide and a two-part product, which uses sodiumchlorite and weak organic acids such as citric acid have been availablefor many years, and have been largely used for industrial, bleaching,oxidizing and surface cleaning applications.

Chlorine dioxide has normally been used in industrial applications suchas the whitening of paper pulp, and other bleaching and oxidizingactivities. More recently chlorine dioxide has been found to beeffective in disinfecting hard surfaces such as countertops and wallsand is promoted to disinfect animal drinking water as well as othersimilar applications. Chlorine dioxide has a noticeable odor similar tochlorine, which is still noticeable at aqueous concentrations as low as10 ppm. People working with high concentrations of chlorine dioxide mustnormally wear personal protective equipment to prevent possible skin andeye contact. Chlorine dioxide reacts with many organic compounds andunder many conditions “active” chlorine dioxide has poor shelfstability. These facts either singularly or in combination normallydissuade most development personnel from considering chlorine dioxide asan additive to personal care products let alone oral care applications.

Recent advances have made chlorine dioxide available for use in a fewniche oral care mouthwashes and toothpastes, which strive to control badbreath by destroying the bacteria that causes bad breath. Examples ofthese commercial oral uses are CloSYS® oral rinse and toothpaste,DioxiRinse™ mouthwash, DioxiBrite™ toothpaste and ultraDEX® oral rinseto name a few. The bacteria reduction asserted to occur through use ofthese products is also said to reduce plaque. These products also claimadditional teeth whitening effects due to the oxidation of dental stainsby chlorine dioxide. Chlorine dioxide containing toothpastes and mouthrinses may marginally lessen the rate of tartar build up by destroyingbacteria and plaque. But neither chlorine dioxide by itself nor anycommercially available formulations are effective in removing tartarfrom teeth. Instead, they have been found to be ineffective in removingtartar.

Accordingly, there has been a long-felt but unmet need for a product ormethod that allowed an individual to actively remove accumulated tartarand plaque from one's teeth between professional cleanings.

SUMMARY

In an aspect, the invention relates to an oral care formulationcomprising at least one dianhydrohexitol and at least one of activechlorine dioxide or stabilized chlorine dioxide.

In an aspect, the invention relates to an oral care formulationcomprising at least one of DMI, one or more equivalents of DMI, or oneor more analog of DMI in combination with at least one of activechlorine dioxide or stabilized chlorine dioxide.

In an aspect, the invention relates to a method for treating tartar onfillings, crowns, dental appliances, or teeth or adjacent to gums of asubject. The method comprises applying an oral care formulationcomprising at least one dianydrohexitol and at least one of activechlorine dioxide or stabilized chlorine dioxide to at least one of thefillings, crowns, dental appliances, teeth, gums, or oral cavity of thesubject.

In an aspect, the invention relates to a method for treating tartar onfillings, crowns, dental appliances, or teeth or adjacent to gums of asubject. The method comprises applying an oral care formulationcomprising at least one of DMI, one or more equivalents of DMI, or oneor more analog of DMI in combination with at least one of activechlorine dioxide or stabilized chlorine dioxide to at least one of thefillings, crowns, dental appliances, teeth, gums, or oral cavity of saidsubject.

In an aspect, the invention relates to a method for inhibiting theformation of tartar, bacteria, plaque, biofilm and periodontal diseasein the oral cavity of a subject. The method comprises applying an oralcare formulation comprising at least one dianhydrohexitol and at leastone of active chlorine dioxide or stabilized chlorine dioxide to the atleast one of the teeth, gums, or oral cavity of the subject.

In an aspect, the invention relates to a method for inhibiting theformation of tartar, bacteria, plaque, biofilm and periodontal diseasein the oral cavity of a subject. The method comprises applying an oralcare formulation comprising at least one of DMI, one or more equivalentsof DMI, or one or more analog of DMI in combination with at least one ofactive chlorine dioxide or stabilized chlorine dioxide to at least oneof the teeth, gums, or oral cavity of the subject.

In an aspect, the invention relates to a method for preparing an oralcare formulation an oral care formulation comprising at least onedianydrohexitol and at least one of active chlorine dioxide orstabilized chlorine dioxide. The method comprises forming the activechlorine dioxide immediately before use of the oral care formulation bymixing a composition comprising the stabilized chlorine dioxide and pHstabilizers with a separate composition comprising a weak acid. Themethod may further comprise mixing the active chlorine dioxide with atleast one of the at least one dianydrohexitol or water before or duringuse of the oral care formulation.

In an aspect, the invention relates to a method for preparing an oralcare formulation an oral care formulation comprising at least one ofDMI, one or more equivalents of DMI, or one or more analog of DMI incombination with at least one of active chlorine dioxide or stabilizedchlorine dioxide. The method comprises forming the active chlorinedioxide immediately before use of the oral care formulation by mixing acomposition comprising the stabilized chlorine dioxide and pHstabilizers with a separate composition comprising a weak acid. Themethod may further comprise mixing the active chlorine dioxide with atleast one of water and the at least one of DMI, one or more equivalentsof DMI, or one or more analog of DMI before or during use of the oralcare formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of embodiments of the presentinvention will be better understood when read in conjunction with theappended drawings. For the purpose of illustrating the invention, thereare shown in the drawings embodiments which are presently preferred. Itis understood, however, that the invention is not limited to the precisearrangements and instrumentalities shown. In the drawings:

FIG. 1A illustrates gum pocket depth measurements around healthy gums.

FIG. 1B illustrates gum pocket depth measurement in a periodontalpocket.

FIGS. 2A-2E illustrate progression of maladies from healthy teeth andgums to advanced periodontitis. FIG. 2A illustrates healthy teeth andgums. FIG. 2B illustrates gingivitis. FIG. 2C illustrates earlyperiodontitis. FIG. 2D illustrates moderate periodontitis. FIG. 2Eillustrates advanced periodontitis.

FIG. 3 illustrates reductions in gum pocket depth measurements.

FIG. 4 illustrates reductions in gum pocket depth measurements.

FIG. 5 illustrates reductions in gum pocket depth measurements.

FIG. 6 illustrates removal of material from teeth before and aftertreatment with an oral care formulation herein.

FIG. 7 illustrates removal of material from teeth before and aftertreatment with an oral care formulation herein.

FIG. 8 illustrates optimized structures of five of the glucan networkexpanders.

FIG. 9 illustrates 2,4,6-branched glucan heptamer,-(αDGlc(1-3)αDGlc(1-3)[(1-6)αDGlc])3αDGlc-.

FIG. 10 illustrates the structure of a complex between dimethylisosorbide (DMIS) and a model glucan target.

FIG. 11 illustrates a representation of a tartar formation timeline.

FIG. 12 illustrates tartar buildup with chlorine dioxide and no DMI.

FIG. 13 illustrates tartar buildup after treatment with dimethylisosorbide mixed with common tartar reducing toothpastes, but withoutchlorine dioxide.

FIG. 14 illustrates shows tartar levels after treatment with an oralcare formulation including DMI and chlorine dioxide before a cleaning bya dental hygienist.

FIG. 15 illustrates tartar levels after treatment with an oral careformulation including DMI and chlorine dioxide after the cleaning by thedental hygienist.

FIG. 16 illustrates tartar levels after mouthwash treatments with 5.49%DMI, 0.01% chlorine dioxide and 94.5% water (total weight 3.17 g).

FIG. 17 illustrates tartar levels after mouthwash treatments followingthe treatment of FIG. 16 but with 15.1% DMI, 0.0085% chlorine dioxide,and 84.8% water (total weight 3.065 g).

DETAILED DESCRIPTION

Certain terminology is used in the following description for convenienceonly and is not limiting. The words “right,” “left,” “top,” and “bottom”designate directions in the drawings to which reference is made. Thewords “a” and “one,” as used in the claims and in the correspondingportions of the specification, are defined as including one or more ofthe referenced item unless specifically stated otherwise. A number ofterms are defined below.

The term, “teeth,” refers to natural teeth and any other hard surfaces,such as crowns, caps, fillings, bridges, dental implants, and the like,that are fixed within the oral cavity and cleansed in situ within theoral cavity of a subject.

The terms “tartar” and “calculus” refer interchangeably to mineralizeddental plaque and/or biofilms.

The terms “equivalent” and “equivalents” refer to certain compoundsrelated to dimethyl isosorbide (DMI) that have some similar chemicalproperties, which may be substituted for some or all of the DMI in theembodiments. An equivalent may be isosorbide; methyl isosorbide (MI);isomannide; methyl isomannide; dimethyl isomannide; isoidide; methylisoidide; dimethyl isoidide; isodulcide; methyl isodulcide; or dimethylisodulcide. An equivalent may also be selected from ethers, polyethers,and polyols. The polyols may include at least one of the following:erythritol, xylitol, arabitol and ribitol, and their mono methyl;dimethyl; and trimethyl ethers. A polyol may be present alone or asmixtures of with at least one of other polyols or their mono anydrocyclic ethers. Mono cyclic anhydro ethers that may be in combinationwith one or more polyol may be but are not limited to1,4-anhydroerythritol, 1,4-anhydrothreitol, 1,5-anhydroxylitol,1,4-anhydroxylitol, 1,4-anhydroarabitol, 1,5-anhydroarabitol,1,4-anhydroribitol, or 1,5-anhydroribitol. The mono anhydro cyclic anddi anhydro cyclic ethers can also be compounds where at least one of thepoly alcohol functionalities (R—OH) can remain as an alcohol (R—OH) orcan be replaced with methyl ethers (R—OCH₃), ethyl ethers (R—OC2H₅), orisopropyl ethers (R—OCH(CH₃)₂).

The term “analog” of DMI refers to a glucan network expander that ispredicted by the method of Example 4.

The term “effective amount” refers to an amount of an agent or agents(e.g., anti-tartar agent or agents) high enough to significantly improvethe condition to be treated. A significant improvement for a methodherein includes a change in tartar structure to the point where it canbe removed from accessible locations of the oral cavity by brushing witha toothbrush twice each day. The change may be a softening of theconsistency of the tartar. The change may be to tartar in at least oneof subgingival or supragingival locations.

The term “oral care formulation” refers to a topical composition that,in the ordinary course of usage, is not intentionally swallowed forpurposes of systemic administration of particular agents, but is ratherretained in the oral cavity for a time sufficient to contact exposeddental surfaces and/or oral tissues for purposes of oral activity. Theoral care formulation may be in the form of a solution, toothpaste,dentifrice, topical oral gel, mouth rinse, mouthwash, denture treatmentproduct, mouth spray, lozenge, oral tablet, floss, or chewing gum.

The term “orally acceptable carrier” or “pharmaceutically acceptableexcipient” refers to a suitable vehicle, which can be used to apply thepresent oral care formulation to the oral cavity in a safe and effectivemanner. Such vehicles may include materials such as fluoride ion sources(also known as fluoride providing compounds), additional anti-tartaragents, buffers, abrasive materials, peroxide sources, alkali metalbicarbonate salts, thickening materials, humectants, water, surfactants,titanium dioxide, flavor system, sweetening agents, stevia, xylitol,coloring agents, natural saliva, and mixtures thereof.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The term “treating” means preventing, reducing, and/or removing dentaltartar, thereby preventing, reducing and/or alleviating a dentaldisease.

The term “subgingival” means inside the gums. An oral care formulationmay enter subgingival spaces or pockets, but it is understood thatsupragingival tartar can also be treated with an oral care formulationherein.

The terminology above includes the words above specifically mentioned,derivatives thereof, and words of similar import. The phrase “at leastone” followed by a list of two or more items, such as “A, B, or C,”means any individual one of A, B or C as well as any combinationthereof.

Embodiments herein relate to oral care formulations and methods fortreatment of dental disease in a subject by at least one of reducing,removing, or inhibiting the formation of tartar and plaque on and aroundthe teeth and gums. Embodiments relate to an anti-tartar and anti-plaqueoral care formulation that may be administered topically to the oralcavity of the subject. The oral care formulation may be a dentifrice,solution, toothpaste, gel, cream, mouthwash, spray, dental floss,chewing gum, or lozenge. The oral care formulation may be effective inremoving, reducing, and preventing at least one of supragingival orsubgingival tartar and plaque, but without many of the disadvantagesthat are typically associated with conventional treatments of dentaldisease.

An embodiment provides an oral care formulation. The oral careformulation may be for removing tartar. The oral care formulation may befor the treatment of a dental disease in a subject. The oral careformulation may prevent, reduce, or remove at least one of dental tartaror plaque. In an embodiment, the oral care formulation comprises thecombination of at least one dianhydrohexitol compound with chlorinedioxide (ClO₂) in at least one of its active or stabilized forms. Astabilized form of ClO₂ (also referred to herein as stabilized ClO₂) maybe a chlorite source. The chlorite source may be, for example, sodiumchlorite, potassium chlorite, or calcium chlorite. A stabilized form ofClO₂ may be an alkali metal chlorite (for example, sodium chlorite orpotassium chlorite) or alkaline earth metal chlorites (for example,calcium chlorite or magnesium chlorite). A stabilized form of ClO₂ insolution may comprise water and optionally pH stabilizers. The water maybe purified water. In combination with a weak food, cosmetic grade acidor a plaque acids typically found in oral plaque or biofilm, thechlorite source may provide ClO₂. The weak food cosmetic grade acid orplaque acids may be, for example, acetic acid, formic acid, pyruvicacid, citric acid, lactic acid, sodium bisulfate, or disodium phosphate.An oral care formulation herein may further comprise a weak food orcosmetic grade acid. The dianhydrohexitol compound may be dimethylisosorbide (DMI), an equivalent of DMI, and analog of DMI. The oral careformulation may comprise more than one dianhydrohexitol compound. Themore than one dianhydrohexitol compound may comprise at least one ofDMI, one or more equivalents of DMI, or one or more analog of DMI. Anoral care formulation may comprise at least one of DMI, one or moreequivalent of DMI, or one or more analog of DMI in combination withchlorine dioxide in at least one of its active or stabilized forms.

In an embodiment, the oral care formulation comprises DMI or anequivalent of DMI, ClO₂ in at least one of its active or stabilizedforms, one or more pharmaceutically acceptable carriers, and optionallya weak food or cosmetic grade acid. The pharmaceutically acceptablecarriers may include materials such as fluoride ion sources (also knownas fluoride providing compounds), additional anti-tartar agents,buffers, abrasive materials, peroxide sources, alkali metal bicarbonatesalts, thickening materials, humectants, water, surfactants, titaniumdioxide, flavor system, sweetening agents, xylitol, stevia, coloringagents, natural saliva, and mixtures of two or more thereof.

An embodiment comprises a method for treating tartar and plaque usingany oral care formulation herein. The method comprises applying an oralcare formulation herein to the oral cavity of a subject. The subject maybe any animal having teeth. The subject may be a mammal. The subject maybe a feline, a canine, or a human. Applying may comprise applying aneffective amount of the oral care formulation. The oral care formulationmay be in the form of a solution or suspension. The solution orsuspension may comprise other agents. Applying may comprise topicallyapplying the oral care formulation to the oral cavity of the subject,particularly to at least one of the teeth or gums of a subject. Themethod may further comprise preparing an oral care formulation from twoor more separate solutions or suspensions. Preparing may be conductedprior to or during the applying step. Preparing may comprise combining acombination of at least one dianhydrohexitol compound and ClO₂ in atleast one of its active or stabilized forms with a weak food grade orcosmetic acid. Preparing may comprise combining a dianhydrohexitolcompound with ClO₂ in at least one of its active or stabilized forms.Preparing may comprise combining a weak food grade, cosmetic grade acidor a plaque acid, at least one dianhydrohexitol compound, and ClO₂ in atleast one of its active or stabilized forms in any order of addition.The dianhydrohexitol compound may be dimethyl isosorbide (DMI) or anequivalent of DMI. The oral care formulation applied may comprise morethan one dianhydrohexitol compound. The more than one dianhydrohexitolcompound may comprise at least one of DMI or one or more equivalents ofDMI.

Embodiments of the oral care formulation herein and the method fortreating tartar and plaque herein are very effective in removal of bothsupragingival and subgingival tartar, which may lead to reduction ofdental pockets and gum disease. By removal of supragingival andsubgingival tartar, embodiments herein may lead to healthier gums andthe prevention of tooth loss. With treatment with an effective amount,subgingival and supragingival tartar may be reduced, not present, or notvisible for days, week, months, or even years, thus precluding the needfor quarterly, semiannual or possibly annual dental checkups.

Treatment by a method herein with an effective amount of an oral careformulation may provide a clean teeth feeling after only a few days ofuse. Reduced swelling and redness of gum and cessation of gum bleedingmay occur through treatment. Treatment with an effective amount may leadto gum pocket depth reductions equal to or greater than 1 mm after 5months of use for more than 30% of gum pockets with depths of 3 mm ormore. Treatment may result in a 90% or greater, greater than 90%, or100% reduction in the amount of tartar. The amount of tartar may bemeasured by comparison of the overall quantity of labial and buccaltartar deposits at the gingival margin before and after treatment. Asimilar reduction in interproximal tartar may occur. Treatment mayresult in a change in tartar consistency from a flint like rock hardtartar mass to a soft friable mass which can be removed withnon-metallic tools such as a toothbrush, stimudents, and ultrasonicscalers. Such removal may be relatively easy, compared to dentalscaling. Treatment may result in the hygienist, dentist, or periodontistrecommending a greater time interval for the next appointment. Treatmentmay result in no discomfort in the dental chair during a normal hygienevisit.

In a method of treatment herein, concentrations of agents in the oralcare formulation may be adjusted to be low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical/dental judgment. An upper limit on the amount of DMI, andequivalent of DMI, or an analog of DMI is not known. Chlorine Dioxide isvery reactive to some amine functionality and is a small molecule thatcan quickly migrate through the saliva, biofilm to the surface of theskin if there is enough chlorine dioxide. Chlorine dioxide at 0.01% hasbeen used with no reported problems. At 0.01%, 90% is consumed rapidly,about 30 seconds, and about 99% in a minute. There may be very littlechlorine dioxide left at the end of a 2 minute brush cycle. However,different patients may react differently. A safe amount of an agent(e.g., anti-tartar agent or agents) may vary with the particularcondition being treated, the age and physical condition of the patientbeing treated, the severity of the condition, the duration of treatment,the nature of concurrent therapy, and the particular vehicle from whichthe agent is applied. Increased concentrations of chlorine dioxide havebeen used with no problems. 0.02% and 0.03% chlorine dioxide may beacceptable. The chlorine dioxide concentration could be 0.1% or lower.

It was a surprising and unpredictable discovery that the combination ofDMI or an equivalent of DMI and chlorine dioxide produces a synergisticeffect. The combination is capable of removing accumulated tartar fromthe teeth and gums—something that was previously only possible throughthe physical scraping of the teeth and gums by a dental professionalwith specialized instruments.

An effective amount of an oral care formulation herein may be comprisedof at least 1% (weight) of DMI or an equivalent of DMI and at least 10parts per million by weight of chlorine dioxide. An oral careformulation herein may be comprised of at least 2% (weight) of DMI or anequivalent of DMI and at least 10 parts per million by weight ofchlorine dioxide. The volume of an oral care formulation applied may besufficient to allow coating of the subject's teeth with the oral careformulation. The volume may be sufficient to allow brushing of thesubjects teeth while the oral care formulation is within the subject'soral cavity. The effective amount of an oral care formulation to beemployed therapeutically for the treatment of a dental disease, orremoval of tartar and plaque, may be changes based on a number offactors. The factors include, without limitation, the patient's sex,weight and age, the underlying causes of the condition or disease to betreated, and the formulation, and the potency of the active component.The level of tartar deposits on the teeth and gums is known to varyamong individuals depending on variations in oral bacteria and enzymetypes, age, salivary flow, salivary calcium concentration, pH and manyother factors. Limited studies indicate the effective amount of DMI maybe different for a person with light tartar build up versus heavy tartarbuild up. One study participant who normally had heavy tartaraccumulation experienced some tartar build up at the 5.48% (w) level ofDMI and 0.01% (w) chlorine dioxide in 94.51% (w) water. At the end ofthe 5.48% (w) DMI and 0.01% (w) chlorine dioxide trial, dentalphotographs were taken but the tartar was not removed from the teeth bythe hygienist. At that point, the DMI portion of the formulation waschanged to 15.1% (w). The results of a 15.1% (w) DMI and 0.0085% (w)chlorine dioxide in water 84.9% (w) trial showed that the tartar thatwas deposited in the earlier 5.48% (w) trial was almost completelyremoved with no tartar on the top teeth and minimal residual tartar onthe bottom teeth. A method herein may include iterative treatments withan oral care formulation herein. After an iteration, the results may beassessed and the concentrations of DMI or its equivalents and ClO₂ inits active or stabilized forms may be adjusted to achieve a reduction intartar. An effective amount of an oral care formulation herein maycomprise DMI or an equivalent of DMI at a concentration ranging from 1%(w) to 90% (w) and the concentration of chlorine dioxide, in its activeor stabilized form, ranging from 0.001% (w) to 0.08% (w). The DMI or aDMI equivalent in an oral care formulation herein may be present at aconcentration of at least 1% (w). The concentration may be from 1% (w)to 90% (w). The concentration may be any concentration in the range 1%(w) to 90% (w). DMI or a DMI equivalent in an oral care formulationherein may be present at a concentration in a sub-range of 1% (w) to 90%(w), where the low endpoint of the sub-range is selected from anyinteger value from 1% (w) to 89% (w) and the high endpoint of thesub-range is selected from any integer value from 2% (w) to 90% (w). Theconcentration may be from 1% (w) to 30% (w). The concentration may be 5%(w). The concentration may be 15.1% (w). The concentration may be anyspecific value chosen from concentrations in any of the foregoing rangesand sub-ranges. When more than one DMI or DMI equivalent is present inan oral care formulation, the combined concentration of the all DMIand/or DMI equivalents in the oral care formulation may equal the valuesdescribed immediately above for the concentration of DMI or a DMIequivalent in an oral care formulation herein.

The concentration chlorine dioxide, in its active or stabilized form,may be a concentration selected from 0.001% to 0.08% by weight. Theconcentration may be a concentration in a sub-range of 0.001% to 0.08%by weight, where the low endpoint of the sub-range is selected from anyinteger value from 0.001% to 0.079% by weight, and the high endpoint ofthe sub-range is selected from any value from 0.0011% to 0.08% by weightin 0.001% increments. The concentration of chlorine dioxide in referenceto stabilized chlorine dioxide is expressed as the concentration ofchlorine dioxide, as can be determined by standard assays. For example,the concentration of a chlorine dioxide may be measured by exposing acomposition comprising the stabilized chlorine dioxide to a WaterWorks™Water Quality Test Strip (Chlorine Dioxide Check). This report from thismethod was used with formulations comprising either active chlorinedioxide or stabilized chlorine dioxide to determine the concentration ofchlorine dioxide in the formulation.

An oral care formulation herein may comprise an orally acceptablecarrier. The orally acceptable carrier may comprise one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for topical oral administration. By “compatible,” asused herein, is meant that the components of the composition are capableof being comingled without interaction in a manner which wouldsubstantially reduce the composition's stability and/or efficacy.

An oral care formulation herein may comprise one or more carriers and/orexcipients that may include the usual and conventional components ofdentifrices (including non-abrasive gels and gels for subgingivalapplication), mouth rinses, mouth sprays, dental floss, chewing gums,and lozenges (including breath mints) as more fully describedhereinafter.

The choice of a carrier may be determined by the way the oral careformulation is to be introduced into the oral cavity. If a toothpaste(including non-abrasive tooth gels, etc.) is to be used, then a“toothpaste carrier” may be chosen (e.g., abrasive materials, sudsingagents, binders, humectants, flavoring and sweetening agents, etc.).Exemplary toothpaste carriers are disclosed in U.S. Pat. No. 3,988,433to Benedict. If a mouth rinse is to be used, then a “mouth rinsecarrier” may be chosen (e.g., water, flavoring and sweetening agents,etc.). Exemplary mouth rinse carriers are disclosed in U.S. Pat. No.3,988,433 to Benedict. Similarly, if a mouth spray is to be used, then a“mouth spray carrier” may be chosen, or if a lozenge is to be used, thena “lozenge carrier” may be chosen (e.g., a candy base). Exemplary candybases are disclosed in U.S. Pat. No. 4,083,955, to Grabenstetter et al.If a chewing gum is to be used, then a “chewing gum carrier” may bechosen (e.g., gum base, flavoring and sweetening agents). Exemplarychewing gum carriers are disclosed in U.S. Pat. No. 4,083,955, toGrabenstetter et al. If a sachet is to be used, then a “sachet carrier”may be chosen (e.g., sachet bag, flavoring and sweetening agents). If asubgingival gel is to be used (for delivery of actives into theperiodontal pockets or around the periodontal pockets), then a“subgingival gel carrier” may be chosen. Exemplary subgingival gelcarriers are disclosed in U.S. Pat. Nos. 5,198,220 and 5,242,910, issuedMar. 30, 1993 and Sep. 7, 1993, respectively, and both are to Damani.Carriers suitable for the preparation of oral care formulations hereinare well known in the art. See, for example, U.S. Pat. No. 8,303,938,which is hereby incorporated by reference. Their selection will alsodepend on secondary considerations like taste, cost, and shelfstability, etc.

An embodiment comprises a medicated dental floss or toothpick forcontrolling, reducing, removing, or preventing tartar. The floss ortoothpick comprises an oral care formulation herein. The oral careformulation may be incorporated on or in the dental floss or toothpick.The incorporated oral care formulation may be stable. The incorporatedoral care formulation may be applied at the time of use. An embodimentincludes a method of treating comprising applying an oral careformulation herein with a medicated dental floss or toothpick herein.The method may further comprise incorporating the oral care formulationon or in dental floss or a toothpick to form the medicated dental flossor toothpick at time of treating. A result of flossing action, the oralcare formulation may be deposited to the inter-dental area of the teeth.Examples of making such floss are well known and are disclosed in, forexample, U.S. Pat. No. 5,603,921.

Specific embodiments of an oral care formulations herein are presentedhere show that when DMI and chlorine dioxide are used in effectiveamounts in toothpastes, tooth gels and mouthwashes, they destroy andreduce the rate of formation of bacteria, biofilm, tartar and plaque andmore importantly remove tartar that is already present on the tooth andtooth gum interface. The net effect of this synergistic relationship isa marked reduction of bacteria, biofilm, tartar and plaque and anelimination of tartar, gum irritation and gum bleeding and an overallimprovement in the health and hygiene of the oral cavity.

An embodiment of an oral care formulation herein comprises a toothpasteformulation. The toothpaste formulation may comprise DMI and activechlorine dioxide combined with a basic toothpaste formulation. In anexemplary embodiment, the basic toothpaste formulation (100 g) comprises24.3% (w) glycerin; 70% aqueous sorbitol 48.6% (w) (34.0% (w)sorbitol-dry basis, 14.6% (w) water) 2.7% (w) Zeodent 165 silica; 24.3%(w) Zeodent 116 silica, and 0.1% (w) spearmint oil. 2.6 ml of a 100 ppmchlorine dioxide solution was combined with 0.4 ml of DMI 15.1% (w) in asyringe barrel. The 3 ml of DMI-chlorine dioxide solution was then mixedwith the 1.0 g of the basic toothpaste in the mouth. “Stabilized” or“active” chlorine dioxide at the 0.010% (w) level behaved similarly inthis application. This formulation used a total of 6% (w) silicaabrasives verses the typical toothpaste abrasive level of 50% (w). Thetoothpaste formulation may further comprise additional ingredients. Theadditional ingredients may improve taste, mouth feel, and effectiveness.Additional ingredients may comprises at least one of dental cleanser,water, solvents, stabilizers, coloring agents, flavoring agents,medicaments, astringents, detergents, polishing agents, abrasivessweeteners, gelling agents, thickeners, pigments, and other additives.The toothpaste formulation may be in the form of a paste or gel. Atoothpaste formulation may be a multi-part formulation. The multi-partformulation may be a two part formulation, or a three part formulation.A two part formulation may comprise a part A and a part B. Part A maycomprise 15.1% (w) DMI; 0.0085% (w) active chlorine dioxide and 84.89%(w) of distilled water. This may be prepared by mixing just prior to use2.6 ml of 100 ppm chlorine dioxide with 0.4 ml of DMI. Part B, may be abasic toothpaste formulation. An example of a 100 g basic toothpasteformulation comprises 24.3% (w) glycerin; 70% aqueous sorbitol 48.6% (w)(34.0% (w) sorbitol, 14.6% (w) water) 2.7% (w) Zeodent 165 silica; 24.3%(w) Zeodent 116 silica, and 0.1% (w) spearmint oil. For use, a finalformulation may be prepared by mixing part A and B. For example, 3 mlPart A may be mixed with 1 g of part B in the oral cavity and brushed onthe teeth for 2 minutes and the fluids expelled. “Stabilized” or“active” chlorine dioxide at the 0.0085% (w) level behaved similarly inthis application. This formulation used a total of 6% (w) silicaabrasives verses the typical toothpaste abrasive level of 50%. Thetoothpaste formulation may further comprise additional ingredients.

An embodiment of an oral care formulation herein comprises a mouthwashformulation. The mouthwash formulation comprises DMI and active chlorinedioxide. In an exemplary embodiment, the mouthwash formulation wasprepared by measuring and mixing the chlorine dioxide and DMI in asyringe immediately prior to use. The mouthwash formulation preparedcomprised distilled 84.85% (w) water, 0.0085% (w) chlorine dioxidesourced from CDG Environmental and 15.1% (w) DMI. 3 ml of thisDMI-chlorine dioxide solution may be transferred to the mouth afterflossing and the teeth may then be brushed with a Sonicare toothbrushfor 2 minutes. “Stabilized” and “active” chlorine dioxide at the 100 ppmlevel behaved similarly in this application. This formulation was usedfor three months with no (0%) silica or any other abrasive and showed notartar or plaque residue at the end of the trial. A mouth washformulation may further comprise additional ingredients. The additionalingredients may improve taste, mouth feel. Additional ingredients maycomprise at least one of a dental cleanser, water, solvents,stabilizers, coloring agents, flavoring agents, medicaments,astringents, detergents, sweeteners, gelling agents, thickeners,pigments, and other additives. A mouth wash formulation maybe in theform of a liquid, paste, or gel.

An embodiment comprises a multi-part oral care formulation comprisingcomponents of an oral care formulation herein divided into at least twoseparate compositions supplied in at least two separate containers, onefor each of the at least two separate compositions. One of the separatecompositions may comprise the DMI or an equivalent of DMI. Another ofthe separate compositions may comprise the ClO₂ in at least one of itsactive or stabilized forms. Optionally, the weak food or cosmetic gradeacid, if utilized to convert a stabilized form of ClO₂ to ClO₂, may beincluded in the composition comprising DMI, or in a separate container.

The multi-part oral care formulation may be a two-part oral careformulation comprising components of an oral care formulation hereindivided into two separate compositions supplied in two separatecontainers, one for each of the two separate compositions. In thisembodiment, one of the separate compositions may comprise the DMI or anequivalent of DMI. The other of the separate compositions may comprisethe ClO₂ in at least one of its active or stabilized forms. Optionally,the weak food or cosmetic grade acid, if utilized to convert astabilized form of ClO₂ to ClO₂, may be included in the compositioncomprising DMI.

Embodiments comprising a multi-part oral care formulation may allowforming the active chlorine dioxide immediately before or during use ofthe oral care formulation by mixing the at least two separatecompositions in a container or in the oral cavity. Embodiments of amethod for treating tartar and plaque herein may employ a multi-partoral care formulation and comprise forming the active chlorine dioxideimmediately before or during use of the oral care formulation by mixingthe at least two separate compositions in a container or the oralcavity.

In embodiments comprising a multi-part oral care formulation, a firstcomposition in a first container may comprise at least one alkali metalchlorite (for example, sodium chlorite or potassium chlorite) and/or atleast one alkaline earth metal chlorite (for example, calcium chloriteor magnesium chlorite) and pH stabilizers in water. The water may bepurified. A second composition in a second container may comprise atleast one of a weak acid (such as lactic acid, citric acid, sodiumbisulfate, or disodium phosphate), solvents, stabilizers, and coloringagents, flavoring agents, medicaments, astringents, detergents,sweeteners, gelling agents, thickeners, coloring agents, or otheradditives. DMI or a DMI equivalent may comprise one or both of the firstcomposition or the second composition, or may be in a third compositionin a third container. The concentrations of agents in the separatecompositions may be adjusted so that when equal proportions of theseparate compositions are mixed, the oral care formulation resultingcontains an effective concentration of agents. For example, in thetwo-part embodiment, the two separate compositions may be sufficient togenerate chlorine dioxide at the 10 to 800 ppm range when the first andsecond parts are mixed in equal proportions. The DMI concentration inthe combined compositions, the final oral care formulation, may be anyconcentration for this agent in an oral care formulation herein. The DMIconcentration may be from 1% (w) to 90% (w). The DMI concentration maybe from 1% (w) to 30% (w). Separated compositions to be mixed can takethe forms of solutions, slurries, or gels. A striped toothpaste tubewould be an example of this embodiment. Sodium chlorite and weak acid(or other chlorite source and weak acid pair) could be contained inseparate channels within the toothpaste tube and deliveredproportionately (with DMI or a DMI equivalent in either or bothchannels) via a divided nozzle.

Embodiments of a method for treating tartar and plaque herein maycomprise at least one of the following aspects. The oral careformulation may be mixed with a liquid vehicle and applied to the teethand gums via an orally-acceptable device, such as a toothbrush, cup,oral irrigator or subgingival applicator. The oral care formulation maybe applied regularly to teeth and gums. The regularity may be any periodfound by the user to be acceptable. The regularity may be every day,every other day, from 1 to 3 times daily. Test participants, especiallyheavy tartar producers, have observed an improvement in the “mouth feeland cleanliness” within a week of starting to use this oral careformulation. The oral care formulation may be discharged in a rinsingprocess after application. Residual oral care formulation may linger indental pockets, and may continue to dissolve tartar until dissipated orwashed away.

Embodiments also relate to methods for treating a dental disease bypreventing, reducing, and removing dental tartar from the teeth andgums. The method may comprise any a method for treating tartar andplaque herein. The method may comprise preparing a solution orsuspension from an oral care formulation herein and applying the oralcare formulation as a solution or suspension to the teeth and gums.

It should be understood that the application ranges set forth herein areexemplary only and are not intended to limit the scope of thisinvention. The therapeutically effective amount of the oral careformulation may vary with factors including, but not limited to, theefficacy of the composition, stability of the composition, the severityof the conditions to be alleviated, the age and sensitivity of thesubject to be treated and the like, as will be apparent to a skilledartisan in the field. The amount of administration can also be adjustedas the various factors change over time.

The embodiments herein not only to methods for delivering the presentcompositions to the oral cavity of a human, but also to methods fordelivering the composition to the oral cavity of other animals, e.g.,household pets or other domestic animals, or animals kept in captivity.A method for treating tartar and plaque herein may be performed on anysubject with teeth. The subject may be feline, canine, equine, or human.The subject may be a domestic animal, a wild animal, or an animal keptin captivity. A method for treating a dental disease by preventing,reducing, and removing dental tartar from the teeth and gums may also beperformed on any subject with teeth. The subject may be feline, canineor human. The subject may be a domestic animal, a wild animal, or ananimal kept in captivity.

For example, a method may comprise brushing a dog's mouth, teeth and/orgums with an oral care formulation herein. Another example may comprisebrushing a cat's mouth, teeth and/or gums with the oral careformulation. Brushings may be repeated for a sufficient amount of timeto see a benefit. The method may comprises preparing a solution orsuspension comprising the oral care formulation, which may comprises atleast DMI and chlorine dioxide in a pharmaceutically acceptable carrier,and applying the solution or suspension to the teeth and gums with abrush. The formulation can include flavorings, such as meat, poultry,fish, or malt.

A method of treating animals may comprise delivering an oral careformulation herein incorporated on or in a pet care product. A pet careproduct may be a chew or a toy. A pet care product may comprise an oralcare formulation herein. The oral care formulation may be incorporatedinto a relatively supple but strong and durable material such asrawhide, ropes made from natural or synthetic fibers, and polymericarticles made from nylon, polyester or thermoplastic polyurethane. Asthe animal chews, licks or gnaws the product, the incorporated oral careformulation may be released into the animal's oral cavity into asalivary medium, comparable to an effective brushing or rinsing. Anembodiment comprises a pet care product comprising an oral careformulation herein.

A number of clinical diseases and conditions may be treated using anoral care formulation herein. Subjects who may benefit from treatmentwith an oral care formulation herein include those who suffer fromdental plaque, dental tartar, gum disease, dental pockets, dentalcaries, gingivitis, or periodontitis.

An embodiment comprises a method for treating teeth or gums to reducedental tartar. The method comprises applying to the surface of the teethand/or gums an oral care formulation herein. Applying may comprise anyconventional methods. Applying may comprise irrigating, brushing,spraying, painting, or rinsing of the oral cavity and the like.

It has been found that the oral care formulation of the presentembodiments is very effective in the treatment of subgingival tartar, inaddition to supragingival tartar. The subsequent reduction insubgingival inflammation provides relief to acute oral pain caused byinfection. Further use of the oral formulation has been found to restorehealthy gum tissue to formally inflamed gums within two weeks. Inaddition to oral inflammation reduction, periodontal pocket reductionshave been observed. This process of pocket reduction is the result ofboth upper gum inflammation reduction, and most importantly, dental gumreattachment following subgingival tartar elimination.

Embodiments—The following list includes particular embodiments of thepresent invention. But the list is not limiting and does not excludealternate embodiments, as would be appreciated by one of ordinary skillin the art.

1. An oral care formulation comprising: at least one dianhydrohexitoland at least one of active chlorine dioxide or stabilized chlorinedioxide.

2. The oral care formulation of embodiment 1, wherein the at least onedianydrohexitol comprises at least one of DMI, one or more equivalentsof DMI, or one or more analog of DMI.

3. The oral care formulation of any one or more of embodiments 1-2comprising the one or more equivalents of DMI.

4. The oral care formulation of any one or more of embodiments 1-3comprising DMI.

5. The oral care formulation of any one or more of embodiments 1-4,wherein the DMI is at a concentration of at least 1% (w) and thechlorine dioxide is at a concentration of at least 10 parts per millionby weight, or wherein the DMI is at a concentration of at least 1% (w)and the chlorine dioxide is at a concentration of at least 0.001% (w).

6. The oral care formulation of any one or more of embodiments 1-4,wherein the concentration of the DMI is at a concentration from 1% (w)to 40% (w); or 1% (w) to 30% (w), and the chlorine dioxide is at aconcentration from 10 to 800 parts per million by weight, or wherein theconcentration of the DMI is at a concentration from 1% (w) to 40% (w),or 1% (w) to 30% (w), and the chlorine dioxide is at a concentrationfrom 0.001% to 0.08% by weight.

7. The oral care formulation of any one or more of embodiments 1-2comprising at least one of DMI, isosorbide, methyl isosorbide,isomannide, methyl isomannide, dimethyl isomannide, isoidide, methylisoidide, dimethyl isoidide, isodulcide, dimethyl isodulcide, dimethyl1,4-anhydrothreitol, dimethyl 1,4-anhydroerythritol, xylitol, trimethyl1,4-anhydroxylitol, trimethyl 1,5-anhydroxylitol, trimethyl1,4-anhydroarabitol, trimethyl 1,5-anhydroarabitol, trimethyl1,4-anhydroribitol, trimethyl 1,5-anhydroribitol, diethylisosorbide, anddiethylisomannide.

8. The oral care formulation of embodiment 7, wherein the at least onedianhydrohexitol is at a concentration of at least 1% (w) and thechlorine dioxide is at a concentration of at least 10 parts per millionby weight, or wherein the dianhydrohexitol is at a concentration of atleast 1% (w) and the chlorine dioxide is at a concentration of at least0.001% (w).

9. The oral care formulation of any one or more of embodiments 7-8,wherein the at least one dianhydrohexitol is at a concentration from 1%(w) to 40% (w), or 1% (w) to 30% (w), and the chlorine dioxide is at aconcentration from 10 to 800 parts per million by weight, or wherein theconcentration of the DMI is at a concentration from 1% (w) to 40% (w),or 1% (w) to 30% (w), and the chlorine dioxide is at a concentrationfrom 0.001% to 0.08% by weight.

10. The oral care formulation of any one or more of embodiments 1-9further comprising an orally acceptable carrier.

11. The oral care formulation of any one or more of embodiments 1-9further comprising an orally acceptable carrier without abrasives.

12. The oral care formulation of any one or more of embodiments 1-11,wherein the oral care formulation is a dentifrice.

13. The oral care formulation of any one or more of embodiments 1-12,wherein the oral care formulation is a gel.

14. The oral care formulation of any one or more of embodiments 1-12,wherein the oral care formulation is a mouthwash.

15. The oral care formulation of any one or more of embodiments 1-12,wherein the oral care formulation is a dental floss.

16. The oral care formulation of any one or more of embodiments 1-12,wherein the oral care formulation is a chewing gum.

17. The oral care formulation of any one or more of embodiments 1-12,wherein the oral care formulation is a lozenge.

18. The oral care formulation of any one or more of embodiments 1-17,wherein the active chlorine dioxide is formed immediately before use ofthe oral care formulation by mixing a composition comprising thestabilized chlorine dioxide and pH stabilizers with a separatecomposition comprising a weak acid, wherein the stabilized chlorinedioxide comprises an alkaline metal chlorite.

19. The oral care formulation of any one or more of embodiments 1-18,wherein the active chlorine dioxide is formed immediately before use ofthe oral care formulation by mixing a composition comprising thestabilized chlorine dioxide and pH stabilizers with a separatecomposition comprising a weak acid, wherein the stabilized chlorinedioxide comprises alkaline earth metal chlorite.

20. A method for treating tartar on fillings, crowns, dental appliancesor teeth or adjacent to gums of a subject comprising applying the oralcare formulation of any one or more of embodiments 1-19 to at least oneof the fillings, crowns, dental appliances, teeth, gums, or oral cavityof the subject.

21. The method of embodiment 20, wherein the subject is a mammal.

22. The method of one or both of embodiments 20 and 21, wherein themethod reduces or removes tartar and optionally at least one ofbacteria, plaque, or biofilm from the teeth, gums, and oral cavity of amammal.

23. A method for inhibiting the formation of tartar, bacteria, plaque,biofilm and periodontal disease in the oral cavity of a mammal,comprising the step of applying the oral care formulation of any one ormore of embodiments 1-19 to the teeth, gums, and oral cavity of saidmammal.

24. A method for preparing the oral care formulation of any one or moreof embodiments 1-19 comprising forming the active chlorine dioxideimmediately before use of the oral care formulation by mixing acomposition comprising the stabilized chlorine dioxide and pHstabilizers with a separate composition comprising a weak acid, whereinthe stabilized chlorine dioxide comprises an alkaline metal chlorite.

25. A method for preparing the oral care formulation of any one or moreof embodiments 1-19, wherein the active chlorine dioxide is formedimmediately before use of the oral care formulation by mixing acomposition comprising a stabilized chlorine dioxide and pH stabilizerswith a separate composition comprising a weak acid, wherein thestabilized chlorine dioxide comprises an alkaline earth metal chlorite.

26. A mouthwash comprising DMI and stabilized chlorine dioxide. Plaqueacids may activate the stabilized chlorine dioxide to its active form.

27. A mouthwash where DMI is included in Part A & Part B with Part Acontaining alkali or alkalis metal chlorites and Part B containing afood grade or cosmetic acid which in combination with Part A generatesactive chlorine dioxide. DioxiRinse® consists of two parts which whencombined form active chlorine dioxide.

28. A mouthwash where DMI is contained in either part A or part B asdescribed above and active chlorine dioxide is produced when the twocomponents are mixed.

29. A mouthwash component where the components to form active chlorinedioxide are encapsulated in a powder or pill form or anhydrous DMIslurry or gel and active chlorine dioxide is formed when the pill,slurry or gel is exposed to water in the oral cavity. Dutrion® tabletswould be an example of dry tablets that contain components which whenadded to water for active chlorine dioxide.

30. A toothpaste comprising DMI and stabilized chlorine dioxide. Plaqueacids may activate the stabilized chlorine dioxide to its active form.

31. A toothpaste where DMI is included in part A and part B, with Part Acontaining alkali or alkalis metal chlorites and Part B containing afood grade or cosmetic acid. In combination with part A and part Bgenerates active chlorine dioxide. Dioxibrite® Toothpaste forms activechlorine dioxide when part A and part B are mixed

32. A mouthwash where DMI is contained in either part A or part B asdescribed above and active chlorine dioxide is activated when the twocomponents are mixed.

33. A toothpaste component where the components to form active chlorineare encapsulated in a powder or anhydrous DMI slurry, paste or gel, andactive chlorine dioxide is formed when the powder, slurry or gel isexposed to water in the oral cavity. Dutrion® tablets would be anexample of dry tablets that contain components which when added to waterfor active chlorine dioxide.

34. A combination mouthwash which contains stabilized chlorine dioxide,which is activated by plaque acids and a toothpaste, gel or slurry thatcontains DMI. The two could be combined and used to brush the teeth.

35. A gel, paste, cream or mouthwash comprising an oral care formulationherein that is applied to the teeth and as result, tartar is reduced orremoved through normal daily activities. This embodiment may be wellsuited to animals, but could also be used on humans.

36. An oral care formulation of or recited in any one or more of thepreceding embodiments comprising water.

Further embodiments herein may be formed by supplementing an embodimentwith one or more element from any one or more other embodiment herein,and/or substituting one or more element from one embodiment with one ormore element from one or more other embodiment herein.

EXAMPLES

The following non-limiting examples are provided to illustrateparticular embodiments. The embodiments throughout may be supplementedwith one or more detail from one or more example below, and/or one ormore element from an embodiment may be substituted with one or moredetail from one or more example below. All amounts and proportionsreferred to herein and in the appended claims are percent by weight.

Examples herein combine DMI and chlorine dioxide in toothpastes, gels,and mouthwashes to show that these two components work to give a novel,synergistic effect in controlling bacteria, biofilm, tartar and plaqueand, more significantly, these combinations have been found to removetartar. Based on the results of experimentation with embodiments herein,the following theories were developed. Without being bound to anyparticular theory, it appears that chlorine dioxide functions as a fastacting antibacterial in the biofilm, at the tooth face and at the gumpores, to efficiently destroy bacteria and as a result destroy orseverely weaken the protective structure of biofilm, and plaque. Trialshave shown that approximately 90% of the “active” and “stabilized”chlorine dioxide is consumed within 30 seconds and more than 99.5% isconsumed within 2 minutes of its introduction to the mouth either as apaste or wash. DMI may be acting as a delivery enhancer for chlorinedioxide, making it more effective in penetrating and destroyingbacteria, biofilm, and plaque. Chlorine dioxide's ability to weaken ordestroy the bacteria/biofilm structure may allow DMI greater access tothe exposed tartar. Chlorine dioxide may be largely consumed and maydestroy much of the bacteria and biofilm structure within the first 30seconds of its introduction into the oral cavity, while DMI continues torehydrate and remove tartar for the remaining time of exemplary 2 minutebrushing cycles. Similar tartar reduction may be achieved bysequentially introducing chlorine dioxide to the oral cavity and thenintroducing DMI to the oral cavity. A trial of this sequential additionof chlorine dioxide and DMI showed a reduction in the formation oftartar. Methods herein may comprise sequential addition of DMI or anequivalent of DMI and chlorine dioxide in its active or stabilizedforms, in either order.

DMI, because of its solubility and polarity, may interfere with andpartially reverse the mineralization of tartar. This may occur byenhancing the rehydration of the exposed calcium phosphate in tartar orthe tartar matrix, which would be more readily accessible due to thedegradation of the protective biofilm and plaque by chlorine dioxide.The resulting rehydrated tartar structure may then be more easilyremoved by regular brushing with or without common varieties oftoothpastes. The combination of DMI and chlorine dioxide also appears torehydrate the tooth-tartar interface, causing residual tartar in hiddenportions of the tooth surface to be easily removed in sheets, asreported by a dental hygienist who examined known test participantsfollowing application of the oral care formulations described herein.

The synergistic benefits of combining DMI and chlorine dioxide isfurther demonstrated by similar trials where 7.1% (w) DMI or 0.01% (w)chlorine dioxide were used separately from each other and where therewas no possibility of this synergy. In those trials, this separate useof each compound resulted in a significantly greater amount of tartarbuildup.

Example 1

In the following trials, the results were observed, reviewed, andphotographed with a Schick intraoral digital camera by a dentalhygienist and dentist who had previous knowledge of the conditions ofeach test participants teeth and gums.

A commercially available oral rinse containing approximately 100 ppm ofstabilized chlorine dioxide as measured by WaterWorks™ Water QualityTest Strips was used in the following studies. A trial of mouthwash with5.5% (w) DMI mixed with 0.0094% (w) of a readily available source ofcommercial stabilized chlorine dioxide in 94.5% (w) of water wasconducted. With 5.5% (w) DMI levels in this mouthwash formulation, thetartar levels increased over previous studies at higher DMI levels. Anintraoral photograph was taken of these tartar deposits. The mouthwashformulation was then changed from 5.5% (w) DMI to 15.1% (w) DMI mixedwith 0.0085% (w) of the same stabilized chlorine dioxide in 84.9% (w)water. At 15.1% (w) DMI, the pre-existing tartar levels (deposited whileusing 5.5% (w) DMI) were removed, with no residual tartar on the topteeth and minimal tartar on the bottom teeth. The hygienist commentedthat this was the first time that she had seen a reduction of tartarlevels of this magnitude with simple brushing. Dental photographsshowing the buildup and reduction of tartar levels were taken by thehygienist to document these changes. In this set of mouthwash trials,the same commercially available toothpaste was used after each 30-secondmouthwash rinse cycle.

In another trial, a test participant used a commercially availabletoothpaste containing stabilized chlorine dioxide to which 14% (w) DMIwas added and mixed. This test participant used this 14% (w) DMI and0.0086% (w) stabilized chlorine dioxide containing toothpastecombination for three months and brushed twice per day with an Oral B®electric toothbrush with a 2 minute brush cycle. At the end of threemonths, he and his dentist reported that “there was very light tartarand a little plaque between my teeth.” This user commented “I have hadvery heavy tartar, which is why I get my teeth cleaned every threemonths.” The dentist reported his gums were “the best he's ever seenthem.” Based on this result and a similar result from his next threemonths hygiene visit with his periodontist, his periodontist suggestedhe increase the duration of his cleaning from every 3 months to 5months. This change in durations between cleanings will result in a netsaving of approximately $300.00 per year for this individual alone.

At a low volume list price of $100.00 per Kilogram for DMI, a 14% (w)DMI containing toothpaste could add $2.80 to the price of a 7 oz.toothpaste tube. Bulk pricing for DMI could bring this cost downsignificantly, probably to under $2.00 per tube. Thus, in typical use,DMI could add $6 or $8 dollars to the annual cost of toothpaste. Thepotential cost saving for the improved oral hygiene and reduced dentalvisits would significantly outpace this added cost.

Another separate trial used 15.1% (w) DMI, 0.0085% (w) active chlorinedioxide sourced from CDG Environmental and 84.85% (w) water. One (1)gram of a basic toothpaste formulation was used with this DMI andchlorine dioxide mixture for 2 minutes with a toothbrush. A basictoothpaste formulation was made from a mixture of 48.6% (w) 70% sorbitolsolution (35% (w) Sorbitol dry basis, 13.66% (w) water) 24.3% (w)glycerin, 24.3% (w) abrasive silica, 2.7% (w) thickening silica and 0.1%(w) of 100% natural spearmint oil flavoring. This trial eliminated allthe other typical active components of toothpaste as contributors to theobserved synergistic improvement of dental health and tartar reductionlevels caused by chlorine dioxide and DMI. This formulation did notcontain any solvents, stabilizers, coloring agents, medicaments,astringents, fluorides, detergents, polishing agents, sweeteners,gelling agents, pigments, or other additives used in most commerciallyavailable toothpastes, tooth gels, or mouthwashes. This toothpasteformulation used only humectants, thickeners, a flavoring agent, and ade minimis amount of silica abrasive. Because the amount of silicaabrasive used in this formulation was so insignificant, it probablycould have been excluded without affecting the results. The results ofthis trial showed a similar reduction in tartar levels to that observedin previous studies using stabilized chlorine dioxide and showed,unequivocally, that chlorine dioxide and DMI are all that is needed toeliminate plaque, gum inflammation, gum bleed, and any appreciabletartar build up in the accessible regions of the mouth.

Another separate trial used 15.1% (w) DMI, 0.0085% (w) active chlorinedioxide sourced from CDG Environmental and 84.85% (w) water. This trialeliminated the basic toothpaste formulation and all the other typicalactive components of toothpaste as contributors to the observedsynergistic improvement of dental health and tartar reduction levelscaused by chlorine dioxide and DMI. This formulation did not contain anysolvents, stabilizers, coloring agents, medicaments, astringents,fluorides, detergents, polishing agents, sweeteners, gelling agents,abrasives, humectants thickeners, pigments, or other additives used inmost commercially available toothpastes, tooth gels, or mouthwashes. Theresults of this trial showed a similar reduction in tartar levels tothat observed in previous studies using stabilized chlorine dioxide andabrasives and showed, unequivocally, that chlorine dioxide and DMI areall that is needed to eliminate tartar, plaque, gum inflammation and gumbleeding in the accessible regions of the mouth.

Example 2

Gum Pocket Depth Improvements

It is estimated that more than 75% of Americans over the age of 35 havesome form of gum disease. In its earliest stage, their gums might swelland bleed easily. At its worst, they might lose their teeth. Gum diseaseis broken down into two general classifications, gingivitis andperiodonitis. The difference between gingivitis and periodontal diseaseis that in gingivitis the infectious disease attacks the connectivetissue around the tooth. The bacteria release toxins in the gum pocketswhich trigger the infection. Cytokines cut their way through healthytissue and release collagenase, prostaglandins and interleukin whichdestroy healthy connective tissue. In periodontitis the infectiousdisease has gone past the tissues into the supporting bone of the toothcausing tooth motility leading to permanent tooth loss if notprofessionally treated by a dentist.

In a healthy mouth, a gum pocket can be anywhere from 1-3 millimetersdeep. FIGS. 1A and 1B illustrate a method that a hygienist or dentistuses a periodontal probe to measure gum pocket depths. In FIG. 1A, atooth 105 is illustrated surrounded by healthy gums 110, and in FIG. 1B,a tooth 115 is illustrated surrounded by unhealthy gums 120. A probeallows the dentist to measure, usually in millimeters, from the top ofthe gum pocket to the bottom of the gum pocket. The gradations on aprobe are often set at 1 mm increments. Each gradation may be referredto as a depth marker. As illustrated in FIGS. 1A and 1B, the gradationson a probe 130 and probe 135 transition from light to dark. The probe130 in FIG. 1A is not able to penetrate to the gum line even to thedepth marker 131, and is stopped at the bottom of gum pocket 133. Depthmarker 131 does not approach the gum 110. In contrast, the probe 135 inFIG. 1B penetrates past the depth marker 136 and almost to the marker137 in order to reach to the bottom of gum pocket 138. The bottom of agum pocket is the area where the tissue is connected through ligamentsto the root. This measurement is taken very gently and causes no damageto the delicate gum tissue.

The recordings taken during periodontal probing are recorded onto achart. There are 6 measurements taken for each tooth, 3 on the facialside and 3 on the tongue side. By monitoring the recordings against eachother, the dentists and hygienists are able to determine if any areasare becoming progressively worse, or identify improvements wheretreatments have occurred.

An example of the progression in gum pocket depths is illustrated inFIGS. 2A-2E. FIG. 2A shows healthy teeth and gums; FIG. 2B showsgingivitis, FIG. 2C shows early periodontitis, FIG. 2D shows moderateperiodontitis, and FIG. 2E shows advanced periodontitis. When a toothhas periodontal disease, the gum tissue becomes detached past 3 mm deep.At 1 to 3 mm deep a pocket is considered healthy, while 4 mm or deeperit is considered unhealthy. When connective gum tissue loss occurs, itis also a sign that there is bone loss. Scaling and root planing, or“deep cleaning” of deep pockets is recommended with pocket depthsgreater than 4 mm. Deep pocket cleaning is more involved as its focus isto remove the tartar from all pocket areas, since tartar is thebacteria's “hiding place.” Diligent brushing and flossing cannot removethe tartar from a deep pocket. If left alone, these infections can causemore bone loss and tissue detachment, resulting in tooth loss.

The novel synergies of the formulations and methods discussed hereinremove both supragingival and subgingival (periodontal pocket) tartarwith 2 minute brushings twice daily. The data provided in FIGS. 3, 4,and 5 shows the dramatic and consistent reduction in gum pocket depthafter only 4 and 5 months of twice daily use. In each of FIGS. 3, 4, and5, the y-axis represents the number of gum pockets measurements at noteddepth, the x-axis represents gum pocket depth.

FIG. 3 illustrates reductions in gum pocket depth measurements in ahuman male subject, age 63. A 40.9% reduction in gum pocket depths wasobserved in 5 months. The oral care formulation comprised 10% DMI and100 ppm ClO₂. FIG. 4 illustrates reductions in gum pocket depthmeasurements in a human female subject, age 63. A 40.9% reduction in gumpocket depths was observed in 4 months. The oral care formulationcomprised 14.5% DMI and 100 ppm ClO₂. FIG. 5 illustrates reductions ingum pocket depth measurements for a human female subject, age 63. A35.4% reduction in gum pocket depths was observed in 5 months. The oralcare formulation comprised 12% DMI and 100 ppm ClO₂. This data wasprovided by test participants whose gum pocket depth measurements weremade by different hygienists in non-related dental practices.

As shown in FIGS. 3-5, gum pocket depths of 4 and 5 mm are almosttotally eliminated after only 4 or 5 months of use of DMI and chlorinedioxide in 10%, 12% and 14.5% DMI/100 ppm chlorine dioxide toothpasteformulations. The use of all three of these DMI concentrations resultedin at least 1 mm reductions in gum pocket depths for 35% or more of thegum pocket measurements.

The DMI—chlorine dioxide formulation may cleave peptide linkages as wellas splaying, fragmenting and re-hydrating the insoluble glucans whichprovide the structural matrix (glue) that makes tartar rock hard. Theseactions may facilitate the fragmented colloidal tartar to harmlesslyfloat away from the gum pocket and allow reattachment of the gum to thetooth, thereby reducing gum pocket depths and improving gum health.Examples of these gum pocket depth reductions are shown in the previousthree graphs. Up until this point in time the only effective way ofremoving gum pocket tartar, the hiding place for bacteria, was withscaling and or root planing by a dentist or hygienist.

Example 3

Studies to Colloidal Fragmentation of Tartar

The formation of colloidal fragments from tartar by DMI and chlorinedioxide is demonstrated in the following two trials. Together DMI andchlorine dioxide fragment the insoluble glucan and polypeptide matrixwhich hold tartar together. Neither chlorine dioxide nor DMI bythemselves show the ability to fragment the tartar matrix. Not to beheld to any specific mechanism of action, it would appear that theprimary role of chlorine dioxide is to break polypeptide linkages andprotein polyol linkages. But this ability alone is insufficient fortartar fragmentation. The insoluble glucan matrix also appears toprovide much of the needed glue to keep the tartar intact. Dimethylisosorbide appears to enter the cracks within the insoluble glucanstructure and splay out the glucan structure which in turn promotes theentry of water to re-hydrate the normally insoluble glucan anddestabilize and glucan/biofilm matrix and fragment the tartar structure.Evidence for this rehydration and fragmentation mechanism is provided inthe following two studies.

Centrifuge Study #1

In the first study the subject's teeth were flossed with Reach floss,then flossed with a Waterpik water flosser. After the water flossing thewater was removed from the mouth. 3 ml of distilled water was added tothe mouth and the teeth were brushed with only water for 2 minutes.After the 2 minutes brushing cycle, the water was expelled into a funnelinto a centrifuge tube. The subject's teeth were again flossed with awater flosser and then procedure “A” was followed three more times for atotal of four 2 minute brushing cycles. Each time, the brushings wereexpelled to a new labelled centrifuge for a total of 4 centrifuge tubes.The fifth brushing, after another Waterpic water flossing, used 0.4 mlof DMI in 2.6 ml of 100 ppm chlorine dioxide in water. The teeth werebrushed with this mixture for a 5^(th) time and the brushings weretransferred in the same fashion to a 5^(th) labelled centrifuge tube.The 5 centrifuge tubes were spun down in a centrifuge at a centrifugeforce of 1,350 g for 5 minutes. FIG. 6 shows the results of this study.

Referring to FIG. 6, as can be seen from the sediment concentrated inthe bottoms of the centrifuge tubes that the first four 2 minutes ofbrushing with water removed very little material, most likely softplaque, from the teeth. But in the fifth brushing cycle, when thechlorine dioxide and DMI were used together, the fragmentation of thetartar resulted in the formation of a large amount of solids as acolloidal suspension. When this procedure was used the next day by thesame subject there was very little precipitate in any of the 5centrifuge tubes. The reason for this was there was not enough time (24hours) to allow a measurable amount of tartar to accumulate on theteeth.

Tartar was then allowed to build on the teeth for 6 days by using acommercial tartar controlling toothpaste twice per day without usingeither DMI or chlorine dioxide. On the sixth day centrifuge study #2 wasconducted.

Centrifuge Study #2

In this second study, the teeth were flossed with Reach floss, thenflossed with a Waterpik water flosser. The water risings were removed.After the flossing water was removed, 0.4 ml of DMI in 2.6 ml of 100 ppmchlorine dioxide in water was used for the first brushing. After 2minutes of brushing, the brushings were transfected in the same fashionas before through a funnel to a centrifuge tube. As in Centrifuge Study#1 a water flosser was used between each brushing cycle. For the next 4brushings 3 ml of water were added to the mouth and the teeth brushedwith water only for 2 minutes. After the 2 minutes, the brushings wereexpelled through a funnel to a centrifuge tube. The teeth were flossedwith a Waterpik water flosser as before. Each time the brushings wereexpelled to a new labelled centrifuge for a total of 5 centrifuge tubes.The 5 centrifuge tubes were as spun down at a centrifuge force of 1,350g for 5 minutes.

FIG. 7 shows the results of this study. As can be seen, the combinationof DMI and chlorine dioxide removed copious amounts of plaque and tartarin the first brushing. The following water only brushings continued torelease more tartar in diminishing quantities. The residual DMI andchlorine dioxide in the remaining tartar on the teeth were stillfacilitating fragmentation and rehydration of the insoluble glucanmatrix.

Example 4

Virtual Binding Assay for Glucan Network Expanders

The insolubility of branched (1-3)-α-D glucans that are a majorcomponent or oral biofilms are thought to be due to the stabilizingeffect that the branches have on helical conformations of the glucanbackbone which in turn pack tightly into insoluble glucan networks intartar. On this basis, compounds that can disrupt the stabilizinginfluence of the side chains on the helical structures could be goodcandidates for expanding and fragmenting glucan networks. This couldthen increase the permeability of the glucan network to water andbiological control agents. The virtual assay described belowcomputationally tests the ability of candidate glucan network expandersto bind in the U-shaped pockets formed by neighboring side chains thatextend from a helically twisted glucan backbone that branches at everyother glucose unit. Effective binding to these pockets could correlatewith network expansion and fragmentation.

Structures of Candidate Glucan Network Expanders

The geometries of six possible glucan network expanders (GNEs) werefirst optimized using the Fletcher-Reeves optimizer as implemented inthe HyperChem molecular modeling system. Energies and forces werecalculated using either the semi-empirical AM1 electronic structuremethod, or a CHARMM molecular mechanics force field. The optimizedstructures of five of the glucan network expanders are shown in FIG. 8.The five are: dimethylisosorbide (DMIS), dimethylisom amide (DMIM),trimethylanhydroxylitol (TMAX), dimethylanhydroerythritol (DMAE), andtrimethylglycerol (TMG). The structure of a sixth network expander,diethylisosorbide (DEIS), which is closely related to thedimethylisosorbide (DMIS) is not shown. For reference purposes, thestructure of the all carbon analog of DMIS, diethyloctahydropentalene(DEOHP) was also optimized in the same manner.

Structure of Model Glucan Target

The 2,4,6-branched glucan heptamer,-(αDGlc(1-3)αDGlc(1-3)[(1-6)αDGlc])3αDGlc-, which we use as a modeltarget for the GNEs, is illustrated in FIG. 9. The conformation shownand used was obtained by fully extending the backbone of the heptamer,and then optimizing the structure using the same methods as describedabove for the GNEs. The resultant conformation resembles a comb withthree tines, and the site used for the virtual binding assay was thepocket between the first and second tine.

Binding Energies for Glucan network expanders to Glucan Target

Binding energies, ΔE_(bind), at 0 K for the glucan network expanders(GNEs) to the model 2,4,6-branched glucan heptamer were obtained bytaking the difference in product and reactant energies for the followingreaction.GNE+Glucan→GNE-Glucan

The structures of the reactants and products were optimized using theFletcher-Reeves conjugate gradient method with a termination conditionof 0.5 kcal/Å mol. Starting structures for the GNE-Glucan complexes weredetermined by first manually docking the GNE into the binding pocket toavoid steric clashes and to align for potential hydrogen bonds. Table 1summarizes the results. The ΔE_(Bind) values reported in the AM1 columnwere calculated using energies for reactants and products whosegeometries had been optimized at the AM1 level of approximation. TheΔE_(Bind) values reported in the CHARMM column were calculated usingenergies for reactants and products whose geometries had been optimizedusing the CHARMM molecular mechanics force field with a distancedependent dielectric constant. To locate alternative binding modes forthe GNE-glucan complex with possibly lower energy, molecular dynamicssimulations were then run for a period of 1 picosecond at 300 K, and theresultant structures reoptimized. In most cases a lower energy bindingmode was located by this procedure. Table 1, below, reports bindingenergies for GNEs.

TABLE 1 ΔE_(bind)/(kcal mol⁻¹) Binding Reaction AM1 CHARMM DMIS + glucan→ DMIS-glucan −27.1 −20.22 DEOHP + glucan → DEOHP-glucan −19.5 −9.77DMIM + glucan → DMIM-glucan −23.6 −11.26 TMAX + glucan → TMAX-glucan−25.6 −2.94 DMAE + glucan → DMAE-glucan −25.5 −21.15 DEIS + glucan →DEIS-glucan −29.5 −17.94 TMG + glucan → TMG-glucan −25.0 −12.37

Structures of glucan network expander (GNE)—Glucan Target Complexes.

The structure for the dimethyl isosorbide (DMIS)-glucan complexes asdetermined using the CHARMM method is shown in FIG. 10. In FIG. 10, DMISis docked into the pocket between the terminal and middle glucos-1-ylside chains of the 2,4,6-branched glucan heptamer. Hydrogen bondsbetween DMIS and middle glucosyl side chain, and between DMIS and thirdglucosyl unit of the backbone are shown with dashed arrows. The bindingof the DMIS induces a conformational change in which the glucosyl sidechains have splayed to accommodate the DMIS (compare FIGS. 9 and 10).The relatively rigid DMIS exhibits good shape complementarity to thebinding pocket after the induced conformational change. Two stretchedhydrogen bonds are evident, one donated by a hydroxyl group of aglucosyl side chain to the oxygen of a methoxy group of the DMIS, andthe other from a hydroxyl group of a backbone glucosyl unit to theoxygen in one of the tetrahydrofuran rings. Similar calculations wererepeated for complexes of DMIM, TMAX, DMAE, DEIS, and TMG with thetarget, as well as for DEOHP, the all carbon analog of DMIS. A pair ofhydrogen bonds analogous to those formed by DMIS was observed in themodel for each of the complexes formed by DMIM, TMAX, DMAE, DEIS and TMGwith the 2,4,6-branched glucan heptamer. Based upon ΔG_(Bind) values,DMI, followed closely by DEIS, bound most strongly in the model glucanbinding pocket. DMAE also appears to have an advantage over DMIS as aGNE but entropic factors would seem to lower this advantage. But bothmay are equivalents for DMI.

Free Energy of Binding Calculations

Free energies and entropies of binding for the GNEs were calculatedusing the CHARMM molecular mechanics force field with a distancedependent dielectric constant as implemented in the HyperChem molecularmodeling system. After geometry optimization as described above, thefrequencies from a vibrational analysis were used in standardstatistical mechanical expressions to calculate entropies and freeenergies at 298 K. The binding free energies and entropies as calculatedfrom the differences in these thermodynamic properties for products andreactants are listed in Table 2, below.

TABLE 2 ΔG_(Bind)/ ΔS_(Bind)/(kcal K⁻¹ Binding Reaction (kcal mol⁻¹)mol⁻¹) DMIS + glucan → DMIS-glucan −0.95 −0.049362 DEOHP + glucan →DEOHP- 7.14 −0.075714 glucan DMIM + glucan → DMIM- 10.82 −0.068345glucan TMAX + glucan → TMAX-glucan 18.03 −0.061589 DMAE + glucan → DMAE-10.81 −0.074826 glucan DEIS + glucan → DEIS-glucan 1.33 −0.051774 TMG +glucan → TMG-glucan 13.81 −0.053530

Entropies of binding, ΔS_(Bind), are naturally negative due to losses oftranslational, rotational, and vibrational freedom upon binding, but thedifferences in ΔS_(Bind) between molecules are largely due differencesin reductions in vibrational freedom. Specifically, binding is expectedto restrict internal rotations about exocyclic bonds for some GNEs morethan for others.

Based upon ΔG_(Bind) values, DMIS, followed closely by DEIS, binds moststrongly to the model glucan binding pocket. The difference in thebinding free energies of DMIS and DEOHP (8.09 kcal mol⁻¹) is consistentwith the formation of two intermolecular hydrogen bonds by DMIS that arenot possible for its all hydrocarbon analog, DEOHP. Based upon thecalculations at 0 K reported in Table 1, DMAE appears to have anadvantage over DMIS as a GNE. However, when entropic considerations areconsidered, DMAE falls into the pack of GNEs predicted to be lesseffective. An examination of the DMAE-glucan structure reveals that theDMAE is completely buried in the pocket of the glucan with four C—O bondrotations in the two methoxy groups significantly restricted. On theother hand, only one of the DMIS methoxy groups is buried in the glucanpocket in the DMIS-glucan complex. The buried methoxy group accepts ahydrogen bond that restricts two internal C—O bond rotations, but thesecond methoxy group projects out of the pocket so that its rotation isstill relatively unhindered upon binding.

DMIM, TMAX, DMAE, and DEIS are referred to herein as equivalents of DMI.An analog of DMI may be predicted by using the at least one of themodel, tests, or calculations as in this example. An analog would havesimilar properties as the compounds tested above.

Example 5

Tartar removal and periodontal Gum pocket reduction with non-abrasivebrushing with dimethyl isosorbide and chlorine dioxide.

All photographs in this example were taken by a professional oralhygienist using a Schick intraoral digital camera.

Each minute of each day, saliva is being created in our mouths. Thissaliva contains varying amounts of calcium and phosphate ions, bacteriaand other components in a water solution. Over time bacteria coloniesgrow in number and use carbohydrates to produce a protective layercalled biofilm. This combination of materials lose water (de-hydrate)over time and form plaque which with additional time hardens to formrock hard tartar.

This tartar formation process can be interrupted by using mouthwashes ortoothpastes that destroy bacteria and remove plaques. But between eachof these interruptions by a mouthwash or a toothpaste, the process oftartar formation continues. The rate of tartar formation varies fromindividual to individual because of differences in saliva flow, theconcentration of calcium and phosphate ions and many other personalfactors. Mathematically one could look at this process as an equationwhere T_(24 hour)=K×P where the T_(24 hours) is the tartar amount formedover a 24 hour period and it is related to K where K is a tartarformation constant and where P is a variable factor based on acombination of personal factors such as saliva formation rate and theconcentration of calcium and phosphate ions, pH, bacteria and saccharidesources and concentrations.

A representation of a tartar formation timeline is conceptually depictedin FIG. 11. The graph assumes a professional cleaning at time “0” (8:00AM) and the flossing and brushing of teeth after dinner at 6:00 PM (10hours after cleaning) and again after breakfast at 8:00 AM (24 hours)and the cycle continuing onwards. This conceptual graph assumes all theplaque and bacteria are removed at each flossing/brushing cycle and thattartar, which cannot be removed by brushing, remains on the toothsurface. The graph parallels the actual experience of most individualswith some level of tartar formed each day with that amount varying witheach individual.

There are many toothpastes on the commercial market that claim to“inhibit the formation of tartar” or “fight tartar by reducing plaque.”But no commercial toothpastes claim the ability to remove tartar once ithas formed. In contrast, the oral care formulations and methods hereinhave been shown to remove tartar after it has formed. One populartartar-inhibiting toothpaste, CloSYS® Sulfate-Free Fluoride Toothpaste,claims to kill 99.9% of germs that cause bad breath, dissolve unwantedcompounds and reduce harmful bacteria in your mouth. It also claims“Anti-Plaque/Anti-Cavity” characteristics, but it does not removetartar.

FIG. 12 show significant tartar buildup at sites 1510, 1511, 1512, 1513,1514, and 1515 after using CloSYS® toothpaste after flossing with Reach®waxed floss and brushing twice per day with a Philips Sonicare®toothbrush with a new compact Diamondclean® head for two minutes. FIG.12 shows there is a significant level of tartar at the base of eachtooth and between the teeth after only three months of use.

In other unsuccessful trials dimethyl isosorbide was mixed with numerouscommon tartar reducing toothpastes. The following picture is typical thefailed result of six months of flossing with Reach® waxed floss andbrushing twice per day with these various tartar reducing toothpasteswith a Philips Sonicare® toothbrush for two minutes. The DMIconcentration in each case was 7.1% (w). As can be seen in FIG. 13,there is a significant level of tartar formed at the lingual base ofeach tooth and between the teeth after six months.

However, when DMI and chlorine dioxide were used together at aneffective concentration for three months (along with twice-dailyflossing and brushing for two minutes), a dramatic and unexpectedreduction in tartar level was observed as shown in the followingphotograph. FIG. 14 shows tartar levels before cleaning, and FIG. 15shows tartar level after cleaning by the hygienist. The white spotspresent in FIGS. 15 and 17 are from enamel erosion from previous yearsof heavy tartar presence and attack of the enamel by bacteria.

In a separate study, 5% (w) DMI was mixed with 0.0094% (w) chlorinedioxide in of water [94.5% (w)]. After flossing the DMI-chlorinedioxide-water mixture was transferred to the mouth of the subject andthe subject brushed the teeth for 2 minutes with Philips Sonicare®.After 6 weeks of flossing and brushing twice per day with theDMI-chlorine dioxide-water mixture, the photograph of FIG. 16 was taken.FIG. 16 shows a build-up of tartar between the lower lingual teeth andsome traces of tartar at the base of the teeth.

After the picture of FIG. 16 was taken the trial formulation was changedfrom 5% (w) to 15% DMI 0.0085% (w) chlorine dioxide in water [84.9%(w)]. This new formulation was used for 8 weeks with the same flossingand brushing regimen used in the first 6 weeks. This study resulted in adramatic reduction in the level of tartar and tartar was removed bysimple brushing without an abrasive. The picture of FIG. 17 shows theremoval of most of the tartar that had been formed using 5% (w) DMI inthe first six weeks then increasing the DMI concentration to 15% (w)while holding the chlorine dioxide concentration constant atapproximately 0.01% (w).

It is important to note that in this trial of 5% (w) and 15% (w) DMI, noabrasive was used to remove tartar. The removal of tartar with orwithout abrasives with simple brushing before this time was notconsidered possible. Further in this example, data are presented thatshow that this combination of DMI and chlorine dioxide not only removestartar above the gum line (supragingival) but also below the gum line(subgingival).

The following studies of tartar removal where the concentration of DMIhas been varied between 0% and 15% in the DMI-chlorine dioxideformulation were conducted:

0% (w) DMI (0.5 to 1 ml of 0.001% (w) chlorine dioxide)—Three months offlossing and brushing with this toothpaste formulation resulted inappreciable hard tartar between the lower lingual front teeth and at thetooth gum line at the lingual base of the teeth. Lower levels of hardtartar were present throughout the tooth surfaces.

2% (w) DMI (0.5-1 ml 0.001% (w) chlorine dioxide)—Three months offlossing and brushing with this toothpaste formulation resulted inappreciable hard tartar between the lower lingual front teeth and at thetooth gum line at the lingual base of the teeth. Soft tartar was presenton the top posterior buccal teeth.

6% (w) DMI (0.5-1 ml 0.001% (w) chlorine dioxide)—Three months offlossing and brushing with this toothpaste formulation resulted in lowlevels of soft tartar between the lower lingual front teeth and at thetooth gum line at the lingual base of the teeth. Soft tartar was presenton the top posterior buccal teeth. The overall tartar levels were lowerthan that experienced with lower levels of DMI.

7% (w) DMI (0.5-5 ml 0.001% (w) chlorine dioxide)—Three and six monthsof flossing and brushing with multiple toothpaste formulations resultedin minimal soft tartar between the lower lingual front teeth and minimalsoft tartar and at the tooth-gum line at the lingual base of the teeth.No or only trace tartar was present on the top posterior buccal teeth.

10% (w) DMI (0.5-2.5 ml 0.001% (w) chlorine dioxide)—Three and six monthof flossing and brushing with this toothpaste formulation resulted intrace or no soft tartar between the lower lingual front teeth and traceor no soft tartar and at the tooth-gum line at the lingual base of theteeth. No tartar was present on the top posterior buccal teeth.

12-15% (w) DMI (0.5-2.5 ml 0.001% (w) chlorine dioxide)—Three and sixmonth of flossing and brushing with this toothpaste formulation resultedin no tartar between the lower lingual front teeth and no tartar and atthe tooth gum line at the lingual base of the teeth. No tartar waspresent on the top posterior buccal teeth. In addition to the completeremoval of tartar above the gum line, users experienced the removal ofsubgingival tartar below the gum line at these and at the 10% (w) DMIlevel. Not only was tartar removed below the gum line, but people withdeep gum pockets experienced significant gum reattachment to theirteeth.

Tartar Removal Based on DMI Concentration

Together DMI and chlorine dioxide appear to fragment the insolubleglucan and polypeptide matrix, which holds the tartar together. Neitherchlorine dioxide nor DMI alone show the ability to fragment this matrix.While not intending to be held to any specific mechanism of action, itappears that the primary role of chlorine dioxide is to breakpolypeptide linkages and protein polyol linkages. This ability alone,however, is insufficient to remove tartar. The water insoluble glucanmatrix appears to provide much of the glue to keep the tartar intact.DMI, however, appears to enter the cracks within the glucan structureand splay out the glucan structure which promotes the entry of water torehydrate the glucan and destabilize and fragment the biofilm andfragment the tartar structure. Thus even at very low concentrations ofDMI some tartar is being removed, but the amount that is being removedis low compared to the rate of normal tartar built up. As the DMIconcentration increases, the hardness of the tartar as reported bydental hygienist decreases. As a result, it is much easier to remove. Atthe same time as the level of DMI increases, the amount of glucans thatare splayed, rehydrated, and fragmented increases as indicated by thesoftening of the tartar and lessening in levels of tartar present on theteeth. When the level of tartar removal is the same or greater than thelevel of tartar creation the dentist or hygienist will report no tartarpresent. For heavy tartar producers, this level of DMI appears to bebetween 8% (w) and 10% (w). For light tartar producers this levelappears to be around 5% (w) or 8% (w) DMI. At levels above 10% (w)preexisting tartar is removed fairly rapidly. One heavy tartar producertrialed DMI at 2% (w) and found hard tartar on the lower teeth afterthree months but the overall level of tartar was less than that found bythe same individual who used 0% (w) DMI. One test participant found that10% (w) DMI with 1 ml of 0.001% (w) chlorine dioxide removed all tartarwhen used only once per day. Other test participants are reportingsimilar findings.

Earlier in this discussion, the tartar formation process was proposed asan equation T_(24 hour)=K×P where the tartar amount formed over a 24hour period is related to K, where K is a tartar formation constant andP, where P represents personal tartar variables such as saliva formationrate and the concentration of calcium and phosphate ions, pH, bacteriaand saccharide sources and concentrations. Based on the tartar removaltrial discussion one could postulate the following simple relationshipas an equation to explain the tartar removal process:T _(current) =T _(24 hour) −T _(removed)

T_(current) is the tartar that is present on the tooth surface

-   -   Value=0 After a professional cleaning    -   Value=0 If T_(24 hour) is less than T_(removed)    -   Value>0 If T_(24 hour) is greater than T_(removed)

T_(24 hour) is the total amount of tartar produced over 24 hours by anindividual. Tartar producers can be loosely grouped into fourcategories: Non tartar producers, light tartar producer, medium tartarproducer and heavy tartar producers. Supersaturation of saliva andplaque fluids with respect to calcium phosphates is the driving forcefor tartar formation. Both salivary flow and plaque pH influence therate of tartar formation. These factors are different for eachindividual.

T_(removed) is the ability of DMI and chlorine dioxide in synergisticcombination to penetrate, rehydrate and fragment tartar so that it canbe washed away in the brushing process with or without abrasives. Thisremoval efficiency is dependent on the levels of DMI and chlorinedioxide.

Chlorine Dioxide Levels

Various chlorine dioxide levels were used to study toothpaste andmouthwash formulations. Chlorine dioxide concentrations typically rangedbetween 0.002% (w) and 0.02% (w) with a limited trial at 0.001% (w).These concentrations were used in a number of mouthwash and toothpasteformulations. The ability to remove or reduce the formation of tartarappeared to be less dependent on the levels of chlorine dioxide than thelevels of DMI. One proposed role for chlorine dioxide is the cleavage ofpolypeptide and peptide glycoside linkages within the tartar matrix.Even at its lowest ranges, chlorine dioxide levels seemed sufficient tocleave critical polypeptide linkages to allow the re hydration andfragmentation of the tartar matrix. Zero (0% (w)) levels of chlorinedioxide were insufficient to allow DMI alone to rehydrate and fragmentthe tartar matrix.

Example 6

Exemplary Veterinary formulations Weight % name Canine/Feline tartarpaste removal formulation 45%  sorbitol 7% Glycerine 5% PEG-600 14% dimethyl isosorbide 0.1%   stabilized chlorine dioxide 1% naturalpoultry flavoring 0.1%   sodium saccharin 0.3%   carboxymethyl cellulose22.5%   Hydrated Silica 5% Titanium Dioxide Variable Disodiumphosphate/Monosodium phosphate buffer Equine tartar removal formulation45%  sorbitol 7% Glycerine 5% PEG-600 14%  dimethyl isosorbide 0.1%  stabilized chlorine dioxide 1% malt flavoring 0.1%   sodium saccharin0.3%   carboxymethyl cellulose 22.5%   Hydrated Silica 5% TitaniumDioxide Variable Disodium phosphate/Monosodium phosphate buffer

The references cited throughout this application are incorporated forall purposes apparent herein and in the references themselves as if eachreference was fully set forth. For the sake of presentation, specificones of these references are cited at particular locations herein. Acitation of a reference at a particular location indicates a manner(s)in which the teachings of the reference are incorporated. However, acitation of a reference at a particular location does not limit themanner in which all of the teachings of the cited reference areincorporated for all purposes.

It is understood, therefore, that this invention is not limited to theparticular embodiments disclosed, but is intended to cover allmodifications which are within the spirit and scope of the invention asdefined by the appended claims; the above description; and/or shown inthe attached drawings. Modifications of the above-described modes forcarrying out the invention that are obvious to persons of skill in theart are intended to be within the scope of the following claims

What is claimed is:
 1. A method for treating a subject comprisingapplying an oral care formulation comprising at least onedianhydrohexitol and at least one of active chlorine dioxide orstabilized chlorine dioxide to at least one of the fillings, crowns,dental appliances, teeth, gums, or oral cavity of the subject, whereinthe at least one dianhydrohexitol is at a concentration of 3% (w) to 90%(w) and said oral care formulation softens dental tartar such that thedental tartar can be removed by brushing.
 2. The method of claim 1,wherein the subject is a mammal.
 3. The method of claim 1, wherein theat least one dianhydrohexitol is dimethyl isosorbide.
 4. The method ofclaim 3, wherein the at least one of active chlorine dioxide orstabilized chlorine dioxide is at a concentration of at least 0.001%(w).
 5. The method of claim 3, wherein the at least one of activechlorine dioxide or stabilized chlorine dioxide is at a concentrationfrom 0.001% (w) to 0.08% (w).
 6. The method of claim 3, wherein thedimethyl isosorbide is at a concentration of 3% (w) to 90% (w), and theat least one of active chlorine dioxide or stabilized chlorine dioxideis at a concentration of at least 0.001% (w).
 7. The method of claim 3,wherein the dimethylisosorbide is at a concentration from 3% (w) to 40%(w); and the at least one of active chlorine dioxide or stabilizedchlorine dioxide is at a concentration from 0.001% (w) to 0.08% (w). 8.The method of claim 3 further comprising brushing the teeth of thesubject.
 9. The method of claim 8, wherein the oral care formulation isa dentifrice.
 10. The method of claim 8, wherein the oral careformulation is a toothpaste.
 11. The method of claim 8, wherein the oralcare formulation is a mouthwash.
 12. The method of claim 1, wherein theat least one dianhydrohexitol is selected from the group consisting ofdimethylisosorbide, isosorbide, methyl isosorbide, isomannide, methylisomannide, dimethyl isomannide, isoidide, methyl isoidide, dimethylisoidide, isodulcide, dimethyl isodulcide.
 13. The method of claim 1,wherein the at least one of active chlorine dioxide or stabilizedchlorine dioxide is at a concentration of at least 0.001% (w).
 14. Themethod of claim 1, wherein the at least one dianhydrohexitol is at aconcentration from 3% (w) to 40% (w); and the at least one of activechlorine dioxide or stabilized chlorine dioxide is at a concentrationfrom 0.001% (w) to 0.08% (w).
 15. The method of claim 1 furthercomprising brushing the teeth of the subject.
 16. The method of claim 1,wherein the oral care formulation is a dentifrice.
 17. The method ofclaim 1, wherein the oral care formulation is a toothpaste.
 18. Themethod of claim 1, wherein the oral care formulation is a mouthwash.